rs11585018

Variant names:

• chr1-11952271-G-A
• rs11585018
• NM_000302.4:c.467-352G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000302.4(PLOD1):​c.467-352G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,204 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (2145 hom., cov: 32)
• Consequence: PLOD1 NM_000302.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 2 publications found

Genes affected

PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PLOD1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, kyphoscoliotic type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.467-352G>A		intron_variant	Intron 4 of 18	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.608-352G>A		intron_variant	Intron 5 of 19		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.467-352G>A		intron_variant	Intron 4 of 18	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20729 AN: 152086 Hom.: 2140 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0828

Gnomad ASJ AF: 0.0880

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.122

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.136 AC: 20762 AN: 152204 Hom.: 2145 Cov.: 32 AF XY: 0.133 AC XY: 9925 AN XY: 74422

African (AFR) AF: 0.288 AC: 11938 AN: 41486

American (AMR) AF: 0.0827 AC: 1265 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0880 AC: 305 AN: 3466

East Asian (EAS) AF: 0.121 AC: 627 AN: 5174

South Asian (SAS) AF: 0.0634 AC: 306 AN: 4828

European-Finnish (FIN) AF: 0.0371 AC: 394 AN: 10616

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0820 AC: 5577 AN: 68012

Other (OTH) AF: 0.120 AC: 253 AN: 2112

Alfa AF: 0.118 Hom.: 296

Bravo AF: 0.146

Asia WGS AF: 0.0920 AC: 320 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.073
DANN	Benign	0.67
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11585018; hg19: chr1-12012328;